Development of novel formulations for mucosal delivery of protein ...

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Figure 6.4: Cumulative permeation curves of INS released from TG-chitosan xerogels showing the effect different EI on permeation through EpiOral TM buccal tissue. ................. 163 Figure 6.5: EpiOral TM tissue viability showing ‘A’ BSA containing chitosan based xerogels with negative (non-treated) and positive (BSA solution) controls. ‘B’ shows the tissue viability of INS containing xerogels along with negative (non-treated) and positive (INS solution) controls. ................................................................................................................... 164 Figure 6.6: Cumulative permeation curves of INS released from TG-chitosan xerogels showing the effect different EI on permeation through sheep buccal tissue. ......................... 165 Figure 6.7: Correlation curves of ‘A’ TG-chitosan-INS and ‘B’ TG-chitosan-APR-INS xerogels using data from EpiOral TM and sheep buccal tissue permeation experiments. ........ 167
CHAPTER ONE INTRODUCTION AND LITERATURE REVIEW 1.1 Overview The buccal mucosa has received increased attention in recent years for the delivery of proteins and peptides as an alternative to the currently used parenteral route (Sudhakar et a l., 2006). Although the buccal mucosa is limited by drug molecular size, hydrophobicity and low membrane permeability, chitosan and its thiolated derivatives have been identified to deliver proteins and peptides via this route because of their mucoadhesive, penetration enhancing and peptidase inhibition properties. Chitosan is a weak cationic polyaminosaccharide derived from deacetylation of the native polymer chitin (Wu et al., 2009), present in shellfish and was discovered 200 years ago (Muzzarelli et al., 2012). Chitosan is composed mainly of (1, 4) linked 2-amino-2- deoxy--D-glucan (Xu et al., 2007), and has been developed as a suitable matrix for the controlled release of protein or peptide drugs over the last two decades (Janes et al., 2001). Formulations with bioadhesive properties have been reported to offer certain advantages for mucosal drug delivery including prolonged residence time, ease of application (Lawlor et al., 1999; Jones et al., 2003) and controlled release of loaded drug. The concept of mucoadhesion has gained significant interest in pharmaceutical technology over the past two decades and might provide opportunities for novel dosage forms, particularly useful for buccal drug delivery (Thanou et al., 2001). Chitosan exhibits mucoadhesive properties and is often used to enhance the residence time of drugs in the mucosal membrane thereby increasing drug bioavailability. The presence of hydrophilicity, functional amino groups, and a net cationic charge has made chitosan a suitable polymer for the ‘intelligent’ delivery of macromolecular compounds, such as proteins and genes. Large changes in functional properties such as swelling in response to small changes in environmental stimuli such as temperature, ionic strength, pH or light explain the intelligent properties of polymers. The ability of a polymer to respond to surrounding environment makes it attractive for use in controlling parameters such as mechanical properties, drug delivery and permeability (Martins et al., 2010). Such intelligent properties of chitosan have been studied by Wu et al., (2006) when they developed a novel hydrogel composed of N-[(2-hydroxy-3-trimethylammonium) propyl] chitosan chloride (HTCC) and glycerophosphate (GP) with a thermo- sensitive sol-gel transition property at body temperature. The chitosan derivative incorporated drug as a stable solution at room temperature but transformed to a transparent hydrogel at body temperature
Page 1 and 2: Greenwich Academic Literature Archi
Page 3 and 4: DECLARATION “I certify that this
Page 5 and 6: ABBREVIATIONS ATR-FT-IR (attenuated
Page 7 and 8: CONTENTS DECLARATION ..............
Page 9 and 10: CHAPTER TWO .......................
Page 11 and 12: CHAPTER FOUR ......................
Page 13 and 14: TABLES Table 1.1: Relationship of i
Page 15 and 16: FIGURES Figure 1.1: Molecular model
Page 17 and 18: [Accessed; 24/05/2012]. ...........
Page 19: Figure 4.2: In-vitro mucoadhesion m
Page 23 and 24: freezing rate at the start of a lyo
Page 25 and 26: aggregates may lead to an immunogen
Page 27 and 28: Figure 1.1: Molecular model of seru
Page 29 and 30: One of the greatest milestones in m
Page 31 and 32: limited success. INS released in a
Page 33 and 34: composition of the delivery system
Page 35 and 36: ioavailability of proteins using pe
Page 37 and 38: 1.3.3.2 Factors affecting mucoadhes
Page 39 and 40: Human salivary glands secrete 1000-
Page 41 and 42: 1.4.2 The nasal route Nasal protein
Page 43 and 44: 1.4.3 The pulmonary route The lungs
Page 45 and 46: and enzymes from foods and beverage
Page 47 and 48: (Veuillez et al., 2001; Nagai, 1986
Page 49 and 50: 1.6.1 Chitosan Chitosan together wi
Page 51 and 52: 1.6.3 Chitosan derivatives The exce
Page 53 and 54: with increasing amounts of immobili
Page 55 and 56: 1.6.6.3 Thiolated chitosans as matr
Page 57 and 58: stability studies among others can
Page 59 and 60: the product matrix, the vacuum of t
Page 61 and 62: an oven at an appropriate temperatu
Page 63 and 64: Several analytical procedures have
Page 65 and 66: transmitting crystal with a high re
Page 67 and 68: 1.8.4.2 Powder diffraction Powder X
Page 69 and 70: 1.8.5.1 Interpreting DSC thermogram
Page 71 and 72:
(absorption in the range 260 to 320
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Figure 1.26: Representation of SEM.
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CHAPTER TWO FORMULATION DEVELOPMENT
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have recommended annealing time of
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Figure 2.1: Chemical structure of c
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model proteins for buccal delivery.
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microemulsion formulation containin
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Table 2.2: Details of consumables u
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chitosan was stirred continuously f
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Table 2.5: Lyophilisation cycles wi
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a b c d Figure 2.6: Photographs of
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simple one step coupling reaction i
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2.3.5 Lyophilisation The primary dr
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The foremost implication of these f
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3.2 Materials and methods 3.2.1 Mat
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were analysed with Agilent Chemstat
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previously tarred 70 µl aluminium
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3.2.13.2 Assay of BSA and INS conte
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A H1 (GluNAc) H3 -H6 NAc H2 (GluNH
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V o V e Intensity ElutionTime (min)
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c c r er % Transmittance 110 90 70
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during the xerogel preparation proc
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and without APR respectively. The r
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3.3.7 Physical stability of BSA and
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15 Circular dichroism (mdeg) 10 5 0
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Since no product melt-back was obse
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0.8 Absorbance ratio 595/450 0.7 0.
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A B Dialysed chitosan-BSA 100 µm 1
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High magnification SEM micrograph o
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BSA content (%) 100.0 80.0 60.0 40.
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conditions leads to protein hydroly
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3.4 Conclusions Analytical characte
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CHAPTER FOUR HYDRATION CAPACITY AND
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4.2.2.1 Effect of formulation proce
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substrate in order to select the op
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Table 4.3 Hydration capacity of xer
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4.3.2.1 Factors affecting mucoadhes
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impacted on the mucoadhesive proper
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and TG-chitosan xerogels. The chito
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PAF (N) TWA (mJ) Cohesiveness (mm)
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Annealed TG-chitosan xerogel simila
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that each model makes assumptions t
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independent difference and similari
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elease profiles plotted. Blank cont
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the second phase of the release pro
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100 Cummulative BSA Release (%) 80
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controlled drug release has been de
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Cummulative INS release (%) 100 80
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that of non-annealed dialysed chito
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Table 5.5: Release parameters obtai
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The effect of formulation processes
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Table 5.9: Model independent differ
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CHAPTER SIX PERMEATION STUDIES USIN
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6.2 Materials and Methods 6.2.1 Mat
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Permeation studies were conducted f
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fold increase in transport of BSA f
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Cumulative INS permeated (g/cm 2 )
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Average percentage viability was pl
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5.5 A TG-chitosan-INS permeation (E
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CHAPTER SEVEN SUMMARY CONCLUSIONS A
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was observed for dialysed and annea
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2. The long-term stability evaluati
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drug delivery systems via the bucca
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33. Bunte, H., Drooge, D.J., Ottjes
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56. Engles, L. 2005. Review and app
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(chitooligosaccharide derivatives)
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of single-point mutants of an amylo
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121. Koschier, F., Kostrubsky, V.,
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142. Liu, W., Wang, D.Q., Nail, S.
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160. Modi, P., Mihic, M. And Lewin,
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180. Pastore, A., Piemonte, F., Loc
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204. Robinson, J., R. 1990. Rationa
Page 215 and 216:
224. Silva, C.A., Nobre, T.M., Pavi
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245. Tamburic, S., Graig, D.Q.M. 19
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265. Wang W. 2000. Lyophilisation a
Page 221 and 222:
285. Zor, T., Selinger, Z. 1996. Li
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APPENDIX B: Manuscripts in preparat
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2. Accepted abstract for podium and
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4. Abstract # 43 awarded podium and
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6. Published abstract M1144 (2011).
Page 231:
8. Published abstract W1470 (2010).
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